This invention relates generally to the field of drug delivery, and in particular to the delivery of pharmaceutical formulations to the lungs. More specifically, the invention relates to the aerosolization of pharmaceutical formulations using energy created by patient inhalation.
Effective drug delivery to a patient is a critical aspect of any successful drug therapy, and a variety of drug delivery techniques have been proposed. For example, one convenient method is the oral delivery of pills, capsules, elixirs and the like. However, oral delivery can in some cases be undesirable in that many drugs are degraded in the digestive tract before they can be absorbed. Another technique is subcutaneous injection. One disadvantage to this approach is low patient acceptance. Other alternative routes of administration that have been proposed include transdermal, intranasal, intrarectal, intravaginal and pulmonary delivery.
Of particular interest to the invention are pulmonary delivery techniques which rely on the inhalation of a pharmaceutical formulation by the patient so that the active drug within the dispersion can reach the distal (alveolar) regions of the lung. A variety of aerosolization systems have been proposed to disperse pharmaceutical formulations. For example, U.S. Pat. Nos. 5,785,049 and 5,740,794, the disclosures of which are herein incorporated by reference, describe exemplary powder dispersion devices which utilize a compressed gas to aerosolize a powder. Other types of aerosolization systems include MDI""s (which typically have a drug that is stored in a propellant), nebulizers (which aerosolize liquids using compressed gas, usually air), and the like.
Another technique which is of interest to the invention is the use of inspired gases to disperse the pharmaceutical formulation. In this way, the patient is able to provide the energy needed to aerosolize the formulation by the patient""s own inhalation. This insures that aerosol generation and inhalation are properly synchronized. Utilization of the patient""s inspired gases can be challenging in several respects. For example, for some pharmaceutical formulations, such as insulin, it may be desirable to limit the inhalation flow rate within certain limits. For example, PCT/US99/04654, filed Mar. 11, 1999, provides for the pulmonary delivery of insulin at rates less than 17 liters per minute. As another example, copending U.S. patent application Ser. No. 09/414,384 describes pulmonary delivery techniques where a high flow resistance is provided for an initial period followed by a period of lower flow resistance. The complete disclosures of all the above references are herein incorporated by reference.
Another challenge in utilizing the patient""s inspired gases is that the inspiration flow rate can drastically vary between individuals. For instance, as shown in FIG. 1, a random sample of 17 individuals which were measured twice a week for four weeks produced flow rates ranging from about 5 liters per minute to about 35 liters per minute. Such variability may affect the ability of the formulation to be dispersed within a gas stream, the ability to deagglomerate a powdered formulation, and/or the ability of the aerosolized formulation to adequately reach the deep lung.
Hence, this invention is related to techniques for regulating the flow of inspired gases that may be utilized when dispersing a pharmaceutical formulation. In one aspect, the invention is related to techniques to enhance the ability of a formulation to be dispersed within a gas stream produced by patient inhalation, to enhance the ability to deagglomerate a powdered formulation, and to enhance the ability of the aerosolized formulation to adequately reach the deep lung.
The invention provides exemplary systems and methods to provide breath actuated, flow regulated aerosol delivery of pharmaceuticals. In one aspect, the invention utilizes the flow of respiratory gases produced by a patient to aerosolize a pharmaceutical formulation. In another particular aspect of the invention, the invention is able to extract a powdered pharmaceutical formulation from a receptacle, deagglomerate the formulation and deliver the formulation to the lungs using a wide range of patient inhalation flow rates. According to another aspect of the invention, devices and methods are provided which provide efficient delivery of a pharmaceutical aerosol to the deep lung.
According to the invention, the flow of respiratory gases may initially be prevented from flowing to the lungs until a predetermined vacuum is produced by the user, at which point the flow of respiratory gases is abruptly initiated. In one particular embodiment, the abrupt initiation of respiratory gas flow is utilized to aerosolize a pharmaceutical formulation. According to this embodiment, respiratory gases are initially prevented from flowing to the lungs when attempting to inhale through an open mouthpiece at one end of the device. The respiratory gases are then abruptly permitted to flow to the lungs after a predetermined vacuum is produced by the user. The flow of respiratory gases is utilized to extract a pharmaceutical formulation from a receptacle and to place the pharmaceutical formulation within the flow of respiratory gases to form an aerosol.
By initially preventing respiratory gases from flowing to the lungs when attempting to inhale, the devices and methods of the present invention provide a way to ensure that the resulting gas stream has sufficient energy to extract the pharmaceutical formulation from the receptacle. In one aspect, the flow of respiratory gases may initially be prevented from flowing to the lungs by placing a valve within an airway leading to the lungs and opening the valve to permit the flow of respiratory gases. According to the invention, the valve is opened when a threshold actuating vacuum caused by the attempted inhalation is exceeded. In this way, when the valve is opened, the resulting gas stream has sufficient energy to extract and aerosolize the pharmaceutical formulation.
In another embodiment, the invention provides an aerosolization device that comprises a housing defining an airway, and a coupling mechanism to couple a receptacle containing a pharmaceutical formulation to the airway. The device further includes a valve to prevent respiratory gases from flowing through the airway until a threshold actuating vacuum is exceeded. At such a time, the valve opens to permit respiratory gases to flow through the airway and to extract the pharmaceutical formulation from the receptacle to form an aerosol.
A variety of threshold valves may be employed to prevent gases from flowing through the airway as will be discussed in detail below. For example, the valve may comprise an occlusion member having an opening, and a pull through member that is pulled through the opening when the threshold actuating vacuum is produced. As one specific example, the occlusion member may comprise an elastically compliant membrane, and the pull through member may comprise a ball that is pulled through the membrane when the threshold vacuum has been achieved. In another aspect, the threshold actuating vacuum of the valve is in the range from about 20 cm H2O to about 60 cm H2O. In one particular aspect, the valve is configured to be disposed within the receptacle. In this way, the valve may conveniently be manufactured along with the receptacle.
According to another aspect, the invention provides devices and methods for regulating the flow of respiratory gases to provide consistent airflow, independent of the breathing rate of the user. In another aspect, the system includes a regulation system to regulate the flow of respiratory gases through the airway after the valve has been opened. The combination of flow regulation with the threshold valve according to the present invention results in devices and methods for aerosol delivery that are effective in delivering the aerosolized formulation to the deep lung.
In still another aspect, the devices and methods of the invention may limit the flow of respiratory gases to a rate that is less than a certain rate for a certain time. For example, the flow rate may be limited to a rate that is less than about 15 liters per minute for a time in the range from about 0.5 second to about 5 seconds, corresponding to a volume in the range from about 125 mL to about 1.25 L. Regulation of the flow rate is advantageous in that it may increase systemic bioavailability of the active agent of certain pharmaceutical formulations via absorption in the deep lung as described generally in PCT Application No. PCT/U.S. 99/04654, filed Mar. 3, 1999 and in copending U.S. application Ser. No. 09/414,384, previously incorporated by reference.
A variety of techniques may be employed to limit or regulate the flow of respiratory gases. For example, feedback may be provided to the user when an excessive flow rate is produced to permit a user to adjust their inhalation rate. Examples of feedback which may be provided include audio feedback, including a whistle, visual feedback, such as indicator lights or a level meter, tactile feedback, such as vibration, and the like. As another alternative, the flow of respiratory gases may be controlled by regulating the size of an airway leading to the lungs. For example, an elastically compliant valve may be used to provide flow resistance based upon the flow rate through the device and limit the flow to a certain rate.
In one aspect, the device further includes a regulation system to regulate the flow of respiratory gases through the airway to a certain rate. For example, the regulation system may be configured to limit the flow to a rate that is less than about 15 liters per minute for a certain time or a certain inspired volume. A variety of flow regulators may be employed to regulate the flow of gases to a certain rate as will be discussed in detail below. For example, the flow regulator may comprise a valve that is constructed of an elastic element, such as a soft elastomer, that limits the flow to a certain rate while also preventing flow in the opposite direction. Such a valve may have an orifice that permits the flow of air through the valve in response to an applied vacuum, and one or more collapsible walls surrounding the orifice. In this way, an increased vacuum pressure level draws the walls toward each other, thereby reducing or closing the orifice area and providing a higher resistance or complete resistance to flow. For example such a valve may be placed in a parallel flow path. Once the flow rate becomes too great, the valve closes so that all air passing through the device must pass through the other flow path. By providing this flow path with a certain size, the flow of gases through the device may be kept below the threshold rate.
In another particular aspect, the regulation system may comprise a feedback mechanism to provide information on the rate of flow of the respiratory gases. For example, the feedback mechanism may comprise a whistle that is in communication with the airway and produces a whistling sound when the maximum flow rate is exceeded. In another alternative, the regulation system may comprise a restriction mechanism to limit the size of the airway. Conveniently, the restriction mechanism may be adjustable to vary the rate of flow of respiratory gases through the airway. The restriction mechanism may be adjusted manually or automatically, such as by the use of an elastically compliant material.
Optionally, an electronically governed, closed-loop control system may be provided to adjust the restriction mechanism. In one aspect, the control system is configured to limit the flow to a certain rate for a certain time or a certain inspired volume and then to sense and adjust the restriction mechanism to permit an increased flow of respiratory gases through the airway. In this manner, the flow rate of respiratory gases may be regulated to limit the flow to a certain rate for a certain time to facilitate proper delivery of the pharmaceutical formulation to the lungs. The control system may then be employed to adjust the restriction mechanism so that the user can comfortably fill their lungs with respiratory gases to deliver the pharmaceutical formulation to the deep lung. Use of the regulation system and control system according to the present invention is advantageous in that the device may be used with numerous users that have different inhalation flow rates, with the device regulating the flow of respiratory gases so that the pharmaceutical formulation is properly delivered to the lungs.
According to another aspect of the invention, after the flow rate has been limited for the desired amount of time or inhaled volume, the size of the airway may be increased to provide for an increased flow rate. This may be accomplished, for example, by opening another airway traveling through the device. In this way, the user may comfortably inhale without substantial resistance in order to fill the user""s lungs with respiratory gases and carry the pharmaceutical formulation into the deep lung.
In an alternative aspect, the invention may optionally utilize a variety of flow integrators to permit an increased flow rate through the inhalation device after a certain amount of time to permit the user to comfortably fill their lungs at the end of the process. Such flow integrators may have one or more moving members that move based on the volume of flow through the device. In this way, when the initial (regulated) volume has been inhaled, the member has moved sufficient to open another gas channel to permit increased gas flow. Examples of flow integrators that may be used are discussed in detail below and include movable pistons, clutch mechanisms, gas filled bellows with a bleed hole, and the like.
The pharmaceutical formulation for use with the systems and methods of the present invention may be a liquid or powder formulation. In one aspect of the method, the pharmaceutical formulation comprises a powdered medicament. The flow of respiratory gases is used to deagglomerate the powder once extracted from the receptacle. Optionally, various structures may be placed into the airway to assist in the deagglomeration process.
In still yet another embodiment, the invention provides a receptacle that comprises a receptacle body defining a cavity that is enclosed by a penetrable access lid. The receptacle further includes a threshold valve that is coupled to the receptacle body. In one aspect, the threshold valve is configured to open when experiencing a vacuum of at least about 40 cm H2O.
According to another aspect, the invention may also utilize a variety of techniques to ensure that the user properly positions their mouth over the mouthpiece during use of an aerosolization device. For example, a lip guard may be included on the mouthpiece to permit the user to place their lips adjacent the lip guard. As another example, the mouthpiece may include bite or other landmarks. Alternatively, one or more holes may be provided in the side of the mouthpiece. These holes must be covered by the lips in order to create a sufficient vacuum to operate the device. As a further example, the mouthpiece may have a circular-to-elliptical profile. The elliptical portion must be covered by the patient""s mouth in order for a vacuum sufficient to actuate the device to be created.